- BICYCLIC COMPOUND AND USE THEREOF
-
The present disclosure relates to a compound derivative containing a 6-7 bicyclic ring and use thereof. The compound according to the present invention can be effectively used in the prevention or treatment of diseases caused by PRMT5 by acting as a PRMT5 inhibitor.
- -
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Paragraph 0548-0549
(2021/04/10)
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- Synthesis of novel pyridine and pyrimidine derivatives as potential inhibitors of HIV-1 reverse transcriptase using palladium-catalysed C-N cross-coupling and nucleophilic aromatic substitution reactions
-
Palladium-mediated cross-coupling reactions are used in the successful construction of a small library of flexible heteroatom-linked diarylpyridine target compounds, including pyridines bearing a secondary amide substituent. Heteroatom-linked diarylpyrimidine derivatives bearing a chlorine substituent are prepared by base-catalysed nucleophilic aromatic substitution reactions without the need for palladium catalysis.
- Changunda, Charles R.K.,Rousseau, Amanda L.,Basson, Adriaan E.,Bode, Moira L.
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p. 152 - 170
(2021/05/27)
-
- Gut-Restricted Selective Cyclooxygenase-2 (COX-2) Inhibitors for Chemoprevention of Colorectal Cancer
-
Selective cyclooxygenase (COX)-2 inhibitors have been extensively studied for colorectal cancer (CRC) chemoprevention. Celecoxib has been reported to reduce the incidence of colorectal adenomas and CRC but is also associated with an increased risk of cardiovascular events. Here, we report a series of gut-restricted, selective COX-2 inhibitors characterized by high colonic exposure and minimized systemic exposure. By establishing acute ex vivo 18F-FDG uptake attenuation as an efficacy proxy, we identified a subset of analogues that demonstrated statistically significant in vivo dose-dependent inhibition of adenoma progression and survival extension in an APCmin/+ mouse model. However, in vitro-in vivo correlation analysis showed their chemoprotective effects were driven by residual systemic COX-2 inhibition, rationalizing their less than expected efficacies and highlighting the challenges associated with COX-2-mediated CRC disease chemoprevention.
- Zhang, Zhuming,Ghosh, Avijit,Connolly, Peter J.,King, Peter,Wilde, Thomas,Wang, Jianyao,Dong, Yawei,Li, Xueliang,Liao, Daohong,Chen, Hao,Tian, Gaochao,Suarez, Javier,Bonnette, William G.,Pande, Vineet,Diloreto, Karen A.,Shi, Yifan,Patel, Shefali,Pietrak, Beth,Szewczuk, Lawrence,Sensenhauser, Carlo,Dallas, Shannon,Edwards, James P.,Bachman, Kurtis E.,Evans, David C.
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p. 11570 - 11596
(2021/07/31)
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- HETEROARYL AMIDES USEFUL AS KIF18A INHIBITORS
-
The present invention relates to chemical compounds having a general formula (I), as defined herein, and synthetic intermediates thereof, which are capable of modulating KIF18A protein thereby influencing the process of cell cycle and cell proliferation to treat cancer and cancer-related diseases. The invention also includes pharmaceutical compositions, including the compounds, and methods of treating disease states related to the activity of KIF18A.
- -
-
Paragraph 0251-0252
(2020/07/14)
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- Discovery of [1,2,4]triazolo[4,3-a]pyridines as potent Smoothened inhibitors targeting the Hedgehog pathway with improved antitumor activity in vivo
-
Triple-negative breast cancer (TNBC), a subset of breast cancers, have poorer survival than other breast cancer types. Recent studies have demonstrated that the abnormal Hedgehog (Hh) pathway is activated in TNBC and that these treatment-resistant cancers are sensitive to inhibition of the Hh pathway. Smoothened (Smo) protein is a vital constituent in Hh signaling and an attractive drug target. Vismodegib (VIS) is one of the most widely studied Smo inhibitors. But the clinical application of Smo inhibitors is limited to adult patients with BCC and AML, with many side effects. Therefore, it's necessary to develop novel Smo inhibitor with better profiles. Twenty [1,2,4]triazolo[4,3-a]pyridines were designed, synthesized and screened as Smo inhibitors. Four of these novel compounds showed directly bound to Smo protein with stronger binding affinity than VIS. The new compounds showed broad anti-proliferative activity against cancer cell lines in vitro, especially triple-negative breast cancer cells. Mechanistic studies demonstrated that TPB15 markedly induced cell cycle arrest and apoptosis in MDA-MB-468 cells. TPB15 blocked Smo translocation into the cilia and reduced Smo protein and mRNA expression. Furthermore, the expression of the downstream regulatory factor glioma-associated oncogene 1 (Gli1) was significantly inhibited. Finally, TPB15 demonstrated greater anti-tumor activity in our animal models than VIS with lower toxicity. Hence, these results support further optimization of this novel scaffold to develop improved Smo antagonists.
- Chen, Mian,Lv, Lin,Quan, Dongling,Schmitz, John C.,Tian, Nannan,Tian, Yuanxin,Wei, Ning,Wu, Huanxian,Wu, Shaoyu,Xie, Ying,Xu, Yimei,Yang, Danni,Yang, Zichao,Zhang, Huiwu,Zhang, Jiajie,Zhang, Tingting,Zhou, Lei
-
-
- Design, synthesis and evaluation of covalent inhibitors of DprE1 as antitubercular agents
-
Decaprenylphosphoryl-β-D-ribose 2′-oxidoreductase (DprE1) is a promising drug target for the development of novel anti-tubercular agents, and inhibitors of DprE1 are being investigated extensively. Among them, the 1,3-benzothiazinone compounds such as BTZ
- Liu, Lingfeng,Kong, Chengcheng,Fumagalli, Marco,Savková, Karin,Xu, Yiwen,Huszár, Stanislav,Sammartino, José C.,Fan, Dongguang,Chiarelli, Laurent R.,Miku?ová, Katarína,Sun, Zhaogang,Qiao, Chunhua
-
-
- Synthesis and in vitro antitumor activity of novel naphthyridinone derivatives
-
A series of naphthyridinone derivatives based on 1a (a precursor of Voreloxin) were designed and synthesized. Seven compounds having >70% inhibition against HL60 at 30 μmol/L were further evaluated for their in vitro antitumor activity by SRB assay. Results reveal that thiazol-2-yl and 3-aminomethyl-4-benzyloxyimino-3-methylpyrrolidin-1-yl groups are optimal at the N-1 and C-7 positions of naphthyridinone core, respectively. 10j exhibits broad-spectrum activity (IC50: 100-fold more potent than the two references against eight of these cell lines.
- Jia, Xue-Dong,Wang, Shuo,Wang, Ming-Hua,Liu, Ming-Liang,Xia, Gui-Min,Liu, Xiu-Jun,Chai, Yun,He, Hong-Wei
-
supporting information
p. 235 - 239
(2017/01/28)
-
- Discovery of a potent, selective, and orally bioavailable acidic 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor: Discovery of 2-[(3 s)-1-[5-(cyclohexylcarbamoyl)-6-propylsulfanylpyridin-2-yl]- 3-piperidyl]acetic acid (AZD4017)
-
Inhibition of 11β-HSD1 is an attractive mechanism for the treatment of obesity and other elements of the metabolic syndrome. We report here the discovery of a nicotinic amide derived carboxylic acid class of inhibitors that has good potency, selectivity, and pharmacokinetic characteristics. Compound 11i (AZD4017) is an effective inhibitor of 11β-HSD1 in human adipocytes and exhibits good druglike properties and as a consequence was selected for clinical development.
- Scott, James S.,Bowker, Suzanne S.,Deschoolmeester, Joanne,Gerhardt, Stefan,Hargreaves, David,Kilgour, Elaine,Lloyd, Adele,Mayers, Rachel M.,McCoull, William,Newcombe, Nicholas J.,Ogg, Derek,Packer, Martin J.,Rees, Amanda,Revill, John,Schofield, Paul,Selmi, Nidhal,Swales, John G.,Whittamore, Paul R. O.
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supporting information; experimental part
p. 5951 - 5964
(2012/08/07)
-
- Discovery of CX-5461, the first direct and selective inhibitor of RNA polymerase I, for cancer therapeutics
-
Accelerated proliferation of solid tumor and hematologic cancer cells is linked to accelerated transcription of rDNA by the RNA polymerase I (Pol I) enzyme to produce elevated levels of rRNA (rRNA). Indeed, upregulation of Pol I, frequently caused by mutational alterations among tumor suppressors and oncogenes, is required for maintenance of the cancer phenotype and forms the basis for seeking selective inhibitors of Pol I as anticancer therapeutics. 2-(4-Methyl-[1,4]diazepan-1-yl)-5-oxo-5H-7-thia-1,11b-diaza-benzo[c] fluorene-6-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide (CX-5461, 7c) has been identified as the first potent, selective, and orally bioavailable inhibitor of RNA Pol I transcription with in vivo activity in tumor growth efficacy models. The preclinical data support the development of CX-5461 as an anticancer drug with potential for activity in several types of cancer.
- Haddach, Mustapha,Schwaebe, Michael K.,Michaux, Jerome,Nagasawa, Johnny,O'Brien, Sean E.,Whitten, Jeffrey P.,Pierre, Fabrice,Kerdoncuff, Pauline,Darjania, Levan,Stansfield, Ryan,Drygin, Denis,Anderes, Kenna,Proffitt, Chris,Bliesath, Josh,Siddiqui-Jain, Adam,Omori, May,Huser, Nanni,Rice, William G.,Ryckman, David M.
-
supporting information; experimental part
p. 602 - 606
(2012/10/08)
-
- Effects of the pyridine 3-substituent on regioselectivity in the nucleophilic aromatic substitution reaction of 3-substituted 2,6-dichloropyridines with 1-methylpiperazine studied by a chemical design strategy
-
A chemical design strategy has been used to select 3-substituted 2,6-dichloropyridines for the nucleophilic aromatic substitution reaction with 1-methylpiperazine. The aim was to study the dependency of the regioselectivity in these reactions on the character of the pyridine 3-substituent expressed by their lipophilicity (PI), size (MR), and inductive effect (Ip). Interestingly, the regioselectivity did not correlate with any of these parameters, but in a statistically significant manner with the Verloop steric parameter B1, as indicated by the p value of 0.006 (R2 = 0.45). This implies that bulky 3-substituents close to the pyridine ring induce regioselectivity towards the 6-position. Useful in practical synthesis is the different regioselectivity obtained with a carboxylic acid 3-substituent and precursors or derivatives thereof. Thus, in acetonitrile as solvent, 3-carboxylate and 3-amide substituents were preferred to obtain the 2-isomer (9:1 ratio of the 6-isomer), whereas the 3-cyano and 3-trifluoromethyl substitutents were preferred to obtain the 6-isomer (9:1 ratio of the 2-isomer). Analysis of the regioselectivity Rsel for the pyridine 2-position in the reaction of 2,6-dichloro-3-(methoxycarbonyl)pyridine with 1-methylpiperazine in 21 different solvents showed that Rsel could be predicted by the Kamlet-Taft equation: Rsel = 1.28990 + 0.03992α - 0.59417β - 0.46169π* (R2 = 0.95, p = 1.9 × 10-10). Rsel is thus mainly correlated with the ability of the solvent to function as a hydrogen-bond acceptor, as expressed by the solvatochromic β parameter. Thus, the 16:1 regioselectivity for the 2-isomer in DCM (β = 0.10) could be switched to a 2:1 selectivity for the 6-isomer in DMSO (β = 0.76). Copyright
- Bach, Peter,Marczynke, Michaela,Giordanetto, Fabrizio
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p. 6940 - 6952
(2013/02/22)
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- ANTINEOPLASTIC DERIVATIVES, PREPARATION THEREOF AND THERAPEUTIC USE THEREOF
-
The disclosure concerns heterobicyclic compounds of general formula (I) and acid addition salts, hydrates and solvates thereof, as well as enantiomers, diastereoisomers and mixtures thereof. Methods for preparing the compounds, pharmaceutical compositions, and methods of treatment also are disclosed.
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Page/Page column 15
(2011/10/19)
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- CONDENSED PYRIDINE DERIVATIVE AND USE THEREOF
-
Provided are a condensed pyridine derivative having a serotonin 5-HT2C receptor activation action, a prophylactic or therapeutic agent for a lower urinary tract symptom, obesity and/or organ prolapse and the like containing the condensed pyridine derivative, a screening method for a substance that increases leak point pressure upon a rise in the intravesical pressure or a prophylactic or therapeutic drug for stress urinary incontinence, a prophylactic or therapeutic drug for cystoceles or enteroceles, containing a substance that activates serotonin 5-HT2C receptor, and a method of screening for a therapeutic drug for cystoceles or enteroceles, including increasing an intravesical pressure after bilateral transection of the hypogastric nerve and pudendal nerve of an animal, and measuring a closure response in the urethra, the rectum or the vagina observed at that time. A serotonin 5-HT2C receptor activator containing a compound represented by the formula: wherein each symbol is as defined in the specification, or a salt thereof.
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Page/Page column 91
(2010/08/18)
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- Discovery and structure-activity relationships of trisubstituted pyrimidines/pyridines as novel calcium-sensing receptor antagonists
-
The trisubstituted pyrimidine 1 was identified through high-throughput screening as a novel calcium-sensing receptor (CaSR) antagonist. Small molecule CaSR antagonists and/or negative allosteric modulators have the potential to act as an anabolic agent for the treatment of osteoporosis. The investigation of structure-activity relationships around 1 resulted in the identification of 18c and 18d, which showed efficacy at promoting PTH release in vivo and exhibited improved potency and solubility over the original lead 1.
- Yang, Wu,Ruan, Zheming,Wang, Yufeng,Van Kirk, Katy,Zhengping, Ma.,Arey, Brian J.,Cooper, Christopher B.,Seethala, Ramakrishna,Feyen, Jean H. M.,Dickson Jr., John K.
-
supporting information; experimental part
p. 1204 - 1208
(2009/12/25)
-
- CHEMICAL COMPOUNDS
-
Compounds of formula (I): wherein variable groups are defined within; their use in the inhibition of 11βHSD1, processes for making them and pharmaceutical compositions comprising them are described.
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-
Page/Page column 34; 40
(2008/12/04)
-
- TETRACYCLIC IMIDAZOLE ANALOGS
-
The present invention provides tetracyclic imidazole analogs which may inhibit cell proliferation and/or induce cell apoptosis. The present invention also provides methods of preparing these compounds, and methods of using the same.
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Page/Page column 56; 57
(2008/12/05)
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- Design, synthesis, and biological evaluation of AT1 angiotensin II receptor antagonists based on the pyrazolo[3,4-b]pyridine and related heteroaromatic bicyclic systems
-
Novel AT1 receptor antagonists bearing the pyrazolo[3,4-b] pyridine bicyclic heteroaromatic system (or structurally related moieties) were designed and synthesized as the final step of a large program devoted to the development of new antihypertensive agents and to the understanding of the molecular basis of their pharmacodynamic and pharmacokinetic properties. The preliminary pharmacological characterization revealed nanomolar AT1 receptor affinity for several compounds of the series and a potent antagonistic activity in isolated rabbit aortic strip functional assay for 7c and 8a. These results stimulated the study of the biopharmaceutical properties of some selected compounds, which were found to be characterized by a permeability from medium to high. Remarkably, the least permeable 7c showed both permeability and oral bioavailability (80%) higher than losartan, but its terminal half-life was shorter. These results suggest that the permeability is not a limiting factor in the pharmacokinetics of these AT1 receptor antagonists.
- Cappelli, Andrea,Nannicini, Chiara,Gallelli, Andrea,Giuliani, Germano,Valenti, Salvatore,Mohr, Galla Pericot,Anzini, Maurizio,Mennuni, Laura,Ferrari, Flora,Caselli, Gianfranco,Giordani, Antonio,Peris, Walter,Makovec, Francesco,Giorgi, Gianluca,Vomero, Salvatore
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p. 2137 - 2146
(2008/12/20)
-
- HYDRAZIDE COMPOUNDS AND USES THEREOF
-
This application relates to certain novel polycyclic compounds that interact with quadruplex-forming regions of polynucleotides and thereby inhibit translation of genetic information into polypeptides. These compounds can thus provide anticancer and antibacterial and antiviral effects. The invention includes novel compounds and pharmaceutical compositions, and methods of using them to treat cancer and other conditions.
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Page/Page column 87
(2008/12/08)
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- Methods of preparing quinolone analogs
-
The present invention relates to the preparation of compounds which are capable of inducing cell death such as apoptotic cell death (apoptosis), and/or for reducing a cell proliferative disorder.
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Page/Page column 21
(2008/06/13)
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- HETEROBICYCLIC COMPOUNDS USEFUL AS P38 KINASE INHIBITING AGENTS
-
Compounds described by the chemical formula (I) or pharmaceutically acceptable salts thereof: (I) are inhibitors of p38 and are useful in the treatment of inflammation such as in the treatment of rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; inflamed joints, eczema, psoriasis or other inflammatory skin conditions such as sunburn; inflammatory eye conditions including conjunctivitis; pyresis, pain and other conditions associated with inflammation.
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Page/Page column 73
(2008/06/13)
-
- 1,6-naphthyridine derivatives and their use to treat diabetes and related disorders
-
The invention relates generally to naphthyridine derivatives of the formula wherein one of U, X, Y and Z is nitrogen and the others are C—R, where R is hydrogen or a substituent. More specifically, the invention relates to 1,6-naphthyridine derivatives and pharmaceutical compositions containing such derivatives. Methods of the invention comprise administration of a naphthyridine derivative of the invention for the treatment of diabetes and related disorders.
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Page/Page column 56
(2010/02/05)
-
- TRISUBSTITUTED HETEROAROMATIC COMPOUNDS AS CALCIUM SENSING RECEPTOR MODULATORS
-
Trisubstituted heteroaromatic compounds having the structure Formula (I) are provided, wherein X is C or N; A and B are each independently CH or N, with the proviso that A and B cannot both be CH; R is Ar-L-; R is hydrogen or alkyl; or R and R can be joined together to form a 4- to 7-membered cycloheteroalkyl ring; R to R, Ar and L are as defined herein. A method for using these compounds to treat diseases associated with abnormal bone or mineral homeostasis is also provided.
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-
-
- Vasopressin agonist formulation and process
-
This invention provides novel formulations for vasopressin agonist compounds, or a pharmaceutically acceptable salt thereof, having the general structure: and processes for making them, the formulations comprising from about 1% to about 20% of active ingredient, from about 1% to about 18% of a surfactant component, from about 50% to about 80% of a component of one or more polyethylene glycols, from about 1% to about 20% of a component of one or more sucrose fatty acid esters and/or polyvinylpyrrolidone and, optionally, one or more preservatives or antioxidants.
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Page/Page column 65
(2010/02/09)
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- 3-PYRROLYL-PYRIDOPYRAZOLES AND 3-PYRROLYL-INDAZOLES AS NOVEL KINASE INHIBITORS
-
Compounds of Formula (I) are useful as mediators of protein kinases and have activity as cell proliferation inhibitors where X, R1-R7 and R9 are as defined herein.
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Page/Page column 65
(2010/02/06)
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- Nicotinamide derivatives as a new class of gastric (H+/K+)-ATPase inhibitors. II. Synthesis and structure-activity relationships of 2-[(2,4- dimethoxyhenzyl)sulfinyl]-N-(4-pyridinyl)pyridine-3-carboxamides
-
Members of a new series of 2-[(2,4-dimethoxybenzyl)sulfinyl]-N-(4- pyridinyl)pyridine-3-carboxamides were synthesized and evaluated for their gastric antisecretory activity and the ability to inhibit cytochrome P450- dependent O-dealkylation of 7-ethoxycoumarin (7-EC) in rat liver microsomes. Several of the compounds synthesized exhibited potent inhibitory activities against both [14C]aminopyrine accumulation stimulated by dibutyryl cyclic AMP in isolated rabbit parietal cells and histamine-induced gastric acid secretion in pylorus-ligated rats when administered intraduodenally; their inhibitory activities were equivalent to or superior to those of the parent compound [2[(2,4-dimethoxybenzyl)sulfinyl]-N-(4-pyridinyl)pyridine-3- carboxamide] and omeprazole. Among the compounds having potent antisecretory activity in vitro and in vivo, 2-[(2,4-dimethoxybenzyl)sulfinyl]-N-(2,5- dimethyl-4-pyridinyl)pyridine-3-carboxamide and 2-[(2,4- dimethoxybenzyl)sulfinyl]-N-(2,6-dimethyl-4-pyridinyl)pyridine-3-carboxamide in particular showed lower inhibitory activity against the 7-EC deethylase than omeprazole. It seems probable that, unlike omeprazole, these compounds do not interact with a metabolism of other drugs in vivo. These compounds, therefore, are considered to be more promising candidate agents for treating acid-related gastrointestinal disorders than the parent compound reported previously.
- Terauchi, Hideo,Tanitame, Akihiko,Tada, Keiko,Nakamura, Keiji,Seto, Yasuhiro,Nishikawa, Yoshinori
-
p. 1027 - 1038
(2007/10/03)
-